Therapeutic reversal of food allergen sensitivity by mature retinoic acid-differentiated dendritic cell induction of LAG3+CD49b-Foxp3- regulatory T cells
Therapeutic reversal of food allergen sensitivity by mature retinoic acid-differentiated dendritic cell induction of LAG3+CD49b-Foxp3- regulatory T cells
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DOI：
10.1016/j.jaci.2016.07.042
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发表时间：
2017-05-01
影响因子：
14.2
通讯作者：
Gordon, John R.
中科院分区：
文献类型：
--
作者：
Dawicki, Wojciech;Li, Chunyan;Gordon, John R.
背景：过敏反应是一种危及生命的疾病，我们的治疗选择有限。虽然食物过敏的特异性免疫疗法越来越有效，但它仍然很费力，并且有很大的不良事件风险。另一方面，调节性树突状细胞（DC）疗法在小鼠过敏性疾病模型中是有效的，并且已经显示出对特应性哮喘患者的T（H）2细胞有效。目的：我们评估DC免疫疗法是否可以逆转小鼠模型中的食物过敏原敏感性，以提供与其在临床中的使用相关的概念证据。我们产生并表征了成熟的视黄酸偏斜树突状细胞（DC-RAs），并评估了它们在小鼠模型中逆转卵清蛋白或花生过敏的能力，以及它们的运作机制。DC-RA表现出成熟但致耐受的表型，表达IL-10、TGF-β、IL-27和醛脱氢酶1A 2，但不表达IL-12或IL-35; IL-10和TGF-β共同驱动它们对T（H）2细胞增殖的抑制。将特异性变应原递呈DC-RA递送至具有卵清蛋白或花生过敏的半数最大致敏小鼠，可降低84%至90%的对口服变应原激发的过敏反应，以及腹泻、肥大细胞活化和T（H）2细胞因子反应和血清变应原特异性IgE/IgG（1）水平。DC-RA表达IL-27对其在体外诱导CD 25（+）淋巴细胞活化基因3（LAG 3）（+）、CD 49 B（-）、叉头盒P3（Foxp 3）（-）调节性T细胞有重要作用，使IL-27 B亚基（Ebi）（-/-）DC-RA类（即IL-27-无能型）在诱导食物过敏原耐受方面无效。我们的数据表明，调节性DC免疫疗法对食物过敏有效，并表明Foxp 3（-）调节性T细胞的诱导可能是在这种情况下诱导耐受的有用策略。
Background: Anaphylaxis is a life-threatening condition for which we have limited therapeutic options. Although specific immunotherapy for food allergies is becoming more effective, it is still laborious and carries substantial risk of adverse events. On the other hand, regulatory dendritic cell (DC) therapy is effective in mouse models of allergic disease and has been shown to work with T(H)2 cells from atopic asthmatic patients.Objective: We assessed whether DC immunotherapy could reverse food allergen sensitivity in mouse models to provide proof of concept relating to their use in the clinic.Methods: We generated and characterized mature retinoic acid-skewed dendritic cells (DC-RAs) and assessed their abilities to reverse ovalbumin or peanut allergies in mouse models, as well as their operative mechanisms.Results: DC-RAs displayed a mature yet tolerogenic phenotype, expressing IL-10, TGF-beta, IL-27, and aldehyde dehydrogenase 1A2 but not IL-12 or IL-35; IL-10 and TGF-beta together drove their suppression of T(H)2 cell proliferation. Delivery of specific allergen-presenting DC-RAs to half-maximally sensitized mice with ovalbumin or peanut allergy reduced anaphylactic responses to oral allergen challenge by 84% to 90%, as well as diarrhea, mast cell activation, and T(H)2 cytokine responses and serum allergen-specific IgE/IgG(1) levels. DC-RA expression of IL-27 was important to their induction of CD25(+) lymphocyte activation gene 3 (LAG3)(+), CD49b(-), forkhead box P3 (Foxp3)(-) regulatory T cells in vitro, such that b subunit of IL-27 (Ebi)(-/-) (ie, IL-27-incompetent) DC-RAs were ineffective in inducing food allergen tolerance.Conclusion: Our data indicate that regulatory DC immunotherapy can be effective for food allergies and suggest that induction of Foxp3(-) regulatory T cells might be a useful strategy for tolerance induction in this context.